CN102731411B - Preparation of 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thioketone and application of same as antidepressant drug - Google Patents
Preparation of 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thioketone and application of same as antidepressant drug Download PDFInfo
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- CN102731411B CN102731411B CN201210198757.7A CN201210198757A CN102731411B CN 102731411 B CN102731411 B CN 102731411B CN 201210198757 A CN201210198757 A CN 201210198757A CN 102731411 B CN102731411 B CN 102731411B
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- HNIUKFIRRIOZDD-UHFFFAOYSA-N CCOC(C(C(c(cc1)ccc1Cl)N1)=C(C)NC1=S)=O Chemical compound CCOC(C(C(c(cc1)ccc1Cl)N1)=C(C)NC1=S)=O HNIUKFIRRIOZDD-UHFFFAOYSA-N 0.000 description 1
- 0 CCOC(C(C(c1c(*)cccc1)N1)=C(C)NC1=S)=O Chemical compound CCOC(C(C(c1c(*)cccc1)N1)=C(C)NC1=S)=O 0.000 description 1
Abstract
The invention relates to application of 4-alkyl-6-aryl-3,4-dihydropyrimidine-2-thioketone as represented by structural formula I and pharmaceutically acceptable salts thereof as antidepressant drugs. In the structural formula I as described in the specification, R1 is selected from the group consisting of C1-C2 alkyl groups and C3-C4 linear-chain alkyl groups and branched-chain alkyl groups, R2 is selected from the group consisting of H, COCH3, CO2CH3, CO2C2H5 and CO2CH2CH2OCH3, X1 is selected from the group consisting of methyl groups, ethyl groups, chlorine, fluorine, hydroxyl groups, methoxy groups, ethoxy groups and nitro groups, and X2, X3 and X4 are selected from the group consisting of methyl groups, ethyl groups, chlorine, bromine, fluorine, hydroxyl groups, methoxy groups, ethoxy groups, nitro groups, sulfonic groups, methanesulfonyl-amino groups, sulfamoyl groups, trifluoromethyl groups and acetyl groups.
Description
Technical field
The present invention relates to a class new compound and in purposes pharmaceutically, specifically 4-alkyl-6-aryl-3,4-dihydro-pyrimidin-2-thioketones is as the application of preparing antidepressant drug.
Background technology
Chinese patent has described aromatic aldehyde, beta-diketon or beta-ketoester and substituting thioureido is prepared pyrimidine mercapto ketone compounds [CN 1803777A, on July 19th, 2006 is open] under the catalysis of trifluoromethanesulfonic acid magnesium; Chinese patent has been described also [3,2-a] pyrimidines synthetic and the application [CN 101348495A, January 21 in 2009 is open] as Bcl-2 family protein antagonist thereof of thiazole; Chinese patent has been described aromatic aldehyde, beta-dicarbonyl compound and urea or thiocarbamide under the catalysis of citric acid, formic acid, acetic acid, oxalic acid etc., room temperature solvent-free reaction obtains 3,4-dihydropyrimidine-2-keto compounds [CN 101367767A, on February 18th, 2009 is open]; Chinese patent has been described the synthetic of 3-carbonyl-6-ethoxycarbonyl-thiazolopyrimidine and the application [CN 101613362A, on December 30th, 2009] as staphylococcus epidermidis signal transduction system YyCG histidine kinase protein inhibitor thereof; Chinese patent has been described
18precursor compound 4-(3-hydroxyl-4-nitrophenyl of F mark tumor inhibitor Monastrol)-5-ethoxycarbonyl-6-methyl-3, the preparation method and its usage [CN 101781259A, on July 21st, 2010 is open] of 4-dihydro-pyrimidin-2-thioketones; Chinese patent has described aromatic aldehyde, beta-dicarbonyl compounds and urea or thiocarbamide synthesizes 3 under the katalysis of organic molecule (R)-tetrahydro thiazole-2-thione-4-carboxylic acid, 4-dihydro-pyrimidin-2-(sulphur) ketone [CN 102225912A, on October 26th, 2011 is open]; Chinese patent described 3,4-dihydropyrimidinonesand/thioketones helicidum derivative preparation and in the application [CN 101475616A, on July 8th, 2009 is open] improving aspect central nervous system function; World patent has been described the synthetic of dihydropyrimidine derivatives and the application [WO 2006097617A, on September 21st, 2006 is open] at anticancer aspect thereof.European patent has been described the synthetic of 5-carboxyl-Isosorbide-5-Nitrae-dihydropyrimidine derivatives and the activity aspect cardiovascular thereof [EP 0202654A2(1), on November 26th, 1986 is open]; World patent has been described the synthetic of Dihydropyrimidines and the application [WO 2006097617A2, on September 21st, 2006 is open] as cancer therapy drug thereof; World patent has been described alkanoic or aromatic aldehyde, (sulphur) urea and beta-dicarbonyl compound synthetic 4,5,6-tri-under the catalysis of five water tin chlorides etc. and has been replaced-3,4-dihydro-pyrimidin-2-(sulphur) ketone [WO 2007105233A2, on September 20th, 2007 is open].
5-HT transporter (SERT) is the important target spot that 5-HT reuptake is relevant, and an existing line antidepressant drug is almost SERT inhibitor; In quick antidepressant drug research, there is scholar to think that sleep deprivation and Adenosine Receptors may be significant for the regulating effect of 5-HT reuptake, and may therefrom find the new compound with quick antidepressant effect, experiment of the present invention finds by the high flux screening means of setting up fluorescent substance ASP the compound that directly acts on SERT or produce 5-HT reuptake inhibition by Adenosine Receptors.
Summary of the invention
The object of the present invention is to provide 4-alkyl-6-aryl-3 shown in chemical structural formula I, 4-dihydro-pyrimidin-2-thioketones and pharmaceutically acceptable salt are as the application of preparing antidepressant drug:
Wherein, R
1be selected from: C
1~ C
2alkyl, C
3~ C
4straight chained alkyl or branched-chain alkyl; R
2be selected from: H, COCH
3, CO
2cH
3, CO
2c
2h
5, CO
2cH
2cH
2oCH
3; X
1be selected from: methyl, ethyl, chlorine, fluorine, hydroxyl, methoxyl group, oxyethyl group, nitro; X
2be selected from: methyl, ethyl, chlorine, bromine, fluorine, hydroxyl, methoxyl group, oxyethyl group, nitro, sulfonic group, methanesulfonamido, sulfamyl, trifluoromethyl, acetoxyl group; X
3be selected from: methyl, ethyl, chlorine, bromine, fluorine, hydroxyl, methoxyl group, oxyethyl group, nitro, sulfonic group, methanesulfonamido, sulfamyl, trifluoromethyl, acetoxyl group; X
4be selected from: methyl, ethyl, chlorine, bromine, fluorine, hydroxyl, methoxyl group, oxyethyl group, nitro, sulfonic group, methanesulfonamido, sulfamyl, trifluoromethyl, acetoxyl group.
The object of the present invention is to provide 4-alkyl-6-aryl-3, the preparation method of 4-dihydro-pyrimidin-2-thioketones: the preparation feedback that it is characterized in that it is as follows:
The present invention compared with prior art tool has the following advantages:
The present invention finds 4-alkyl-6-aryl-3 first, and 4-dihydro-pyrimidin-2-thioketones has antidepressant activity, can be used for preparing antidepressant drug.
Embodiment
Following examples are intended to illustrate the present invention instead of limitation of the invention further.
Embodiment 1
The 6-tertiary butyl-4-(2,4 dichloro benzene base)-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
4,4-dimethyl-1-(2,4 dichloro benzene base)-1-alkene-propione, thiocarbamide and 10%NaOH solution, 20 mL ethanol, back flow reaction, TLC detection reaction, after completion of the reaction, revolve and steam to obtain white product, ethyl alcohol recrystallization obtains the 6-tertiary butyl-4-(2,4 dichloro benzene base)-3,4-dihydro-pyrimidin-2-thioketones, yield 74.5%, m.p.170～172 DEG C.
1h NMR (400 MHz, CDCl
3), δ: 1.06 (s, 9H, 3 × CH
3); 4.77 (d, 1H, J=2.4 Hz, pyrimidine ring 4-H), 5.27 (d, 1H, J=2.4 Hz, pyrimidine ring 5-H), 7.27 (d, 1H, J=8.0 Hz, C
6h
32-H), 7.54 (dd, J=8.0 Hz, J=2.0 Hz, 1H, C
6h
33-H), 7.60 (d, J=2.0 Hz, 1H, C
6h
35-H), 8.85 (s, 1H, NH), 9.33 (s, 1H, NH).
Embodiment 2
The 6-tertiary butyl-4-(4-p-methoxy-phenyl)-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
4,4-dimethyl-1-(4-p-methoxy-phenyl)-1-alkene-propione, thiocarbamide and 10%NaOH solution, 20 mL ethanol, back flow reaction, TLC detection reaction, after completion of the reaction, revolve and steam to obtain white product, ethyl alcohol recrystallization obtains the 6-tertiary butyl-4-(4-p-methoxy-phenyl)-3,4-dihydro-pyrimidin-2-thioketones, yield 68.1%, m.p.177～179 DEG C.
1h NMR (400 MHz, CDCl
3), δ: 1.19 (s, 9H, 3 × CH
3), 3.82 (s, 3H, OCH
3), 4.72 (d, J=3.6 Hz, 1H, pyrimidine ring 5-H), 5.07 (d, J=3.6 Hz, 1H, pyrimidine ring 4-H), 6.45 (s, 1H, NH), 6.91 (m, 2H, C
6h
43,5-H), 7.12 (s, 1H, NH).7.21(m，2H，C
6H
4?2,6-H)。
Embodiment 3
The 6-tertiary butyl-4-(2-p-methoxy-phenyl)-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
4,4-dimethyl-1-(2-p-methoxy-phenyl)-1-alkene-propione, thiocarbamide and 10%NaOH solution, 20 mL ethanol, back flow reaction, TLC detection reaction, after completion of the reaction, revolve and steam to obtain white product, ethyl alcohol recrystallization obtains the 6-tertiary butyl-4-(2-p-methoxy-phenyl)-3,4-dihydro-pyrimidin-2-thioketones, yield 68.1%, m.p.177～179 DEG C.
1h NMR (400 MHz, CDCl
3), δ: 1.19 (s, 9H, 3 × CH
3), 3.82 (s, 3H, OCH
3), 4.72 (d, J=3.6 Hz, 1H, pyrimidine ring 5-H), 5.07 (d, J=3.6 Hz, 1H, pyrimidine ring 4-H), 6.45 (s, 1H, NH), 6.91 (m, 2H, C
6h
43,5-H), 7.12 (s, 1H, NH).7.21(m，2H，C
6H
4?2,6-H)。
Embodiment 4
The 6-tertiary butyl-4-(3,4-Dimethoxyphenyl)-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
Make the 6-tertiary butyl-4-(3,4-Dimethoxyphenyl by the method operation of embodiment 3)-3,4-dihydro-pyrimidin-2-thioketones, 172～175 DEG C of fusing points.
1h NMR (400 MHz, CDCl
3), δ: 1.16 (s, 9H, 3 × CH
3), 3.84 (s, 6H, 2 × OCH
3), 4.73 (m, 1H, pyrimidine ring 5-H), 5.06 (m, 1H, pyrimidine ring 4-H), 6.12 (s, 1H, NH), 6.87 (s, 1H, NH), 6.79-5.84 (m, 3H, C
6h
3).
13c NMR (100MHz, DMSO-d
6), δ: 27.81(3C, 3 × CH
3), 33.41(1C, tertiary carbon), 54.16(1C, pyrimidine ring 6-C), 55.64,55.88(2C, 2 × OCH
3), 96.34(1C, pyrimidine ring 5-C), 110.69,112.12,118.77(3C, phenyl ring 2,5,6-C), 137.25 (1C, phenyl ring 1-C), 143.09,148.48,148.94(3C, pyrimidine ring 4-C, phenyl ring 3,4-C), 174.6(1C, C=S).
Embodiment 5
The 6-tertiary butyl-4-(2-phenelyl)-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
4,4-dimethyl-1-(2-phenelyl)-1-alkene-propione, thiocarbamide and 10%NaOH solution, 20 mL ethanol, back flow reaction, TLC detection reaction, after completion of the reaction, revolve and steam to obtain white product, ethyl alcohol recrystallization obtains the 6-tertiary butyl-4-(4-phenelyl)-3,4-dihydro-pyrimidin-2-thioketones, yield 43.1%, 172～175 DEG C of m.p..
1h NMR (400 MHz, DMSO-d
6), δ: 1.11 (s, 9H, 3 × CH
3), 1.31 (t, J=7.2 Hz, 3H, CH
3), 4.00 (q, J=7.2 Hz, 2H, OCH
2), 4.73 (q, J=4.4 Hz, J=2.4 Hz, 2H, pyrimidine ring 5-H), 4.85 (q, J=4.4 Hz, J=2.4 Hz, 2H, pyrimidine ring 4-H), 6.90 (d, J=8.4 Hz, 2H, C
6h
42,6-H), 7.14 (d, J=8.4 Hz, 2H, C
6h
43,5-H), 8.81 (s, 1H, NH), 9.07 (s, 1H, NH).
Embodiment 6
6-methyl-4-(4-chloro-phenyl-)-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
20 mmol 4-chloro-benzaldehydes, 25 mmol thiocarbamides, 15 mL ethanol and the 0.5 mL vitriol oil, stirring and refluxing, drips 16.6 mmol methyl aceto acetates, TLC monitoring reaction course, react 24 h, cooling reaction solution, separates out white solid, filter, a small amount of ethanol is washed, dry obtain-methyl-4-(4-chloro-phenyl-)-5-ethoxycarbonyl-3,4-dihydro-pyrimidin-2-thioketones, yield 23.7%, 193～195 DEG C of m.p..
Embodiment 7
6-methyl-4-(4-fluorophenyl)-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
40 mmol p-Fluorobenzenecarboxaldehydes, 50 mmol thiocarbamides, 30 mL ethanol and the 1.0 mL vitriol oils, stirring and refluxing, drips 33.3 mmol methyl aceto acetates, TLC monitoring reaction course, react 18 h, cooling reaction solution, separates out beige solid, filter, a small amount of ethanol is washed, dry 6-methyl-4-(4-fluorophenyl)-5-ethoxycarbonyl-3,4-dihydro-pyrimidin-2-thioketones of obtaining, yield 45.1%, 191～192 DEG C of m.p..
Embodiment 8
6-methyl-4-(4-p-methoxy-phenyl)-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
20 mmol aubepine, 25 mmol thiocarbamides, 15 mL ethanol and the 0.5 mL vitriol oil, stirring and refluxing, drips 16.6 mmol methyl aceto acetates, TLC monitoring reaction course, react 15.5 h, cooling reaction solution, separates out pink solid, filter, a small amount of ethanol is washed, dry 6-methyl-4-(4-p-methoxy-phenyl)-5-ethoxycarbonyl-3,4-dihydro-pyrimidin-2-thioketones of obtaining, yield 19.6%, 154～156 DEG C of m.p..
Embodiment 9
6-methyl-4-(4-aminomethyl phenyl)-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
20 mmol p-tolyl aldehydes, 25 mmol thiocarbamides, 20 mL ethanol and the 0.5 mL vitriol oil, stirring and refluxing, drips 16.6 mmol methyl aceto acetates, TLC monitoring reaction course, react 7.5 h, cooling reaction solution, separates out light yellow solid, filter, a small amount of ethanol is washed, dry 6-methyl-4-(4-aminomethyl phenyl)-5-ethoxycarbonyl-3,4-dihydro-pyrimidin-2-thioketones of obtaining, yield 49.0%, 189～192 DEG C of m.p..
Embodiment 10
6-methyl 4-phenyl-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
20 mmol phenyl aldehydes, 25 mmol thiocarbamides, 20 mL ethanol and the 0.5 mL vitriol oil, stirring and refluxing, drips 16.6 mmol methyl aceto acetates, TLC monitoring reaction course, react 20.5 h, cooling reaction solution, separates out white solid, filter, a small amount of ethanol is washed, the dry 6-methyl 4-phenyl-5-ethoxycarbonyl 3,4-dihydro-pyrimidin-2-thioketones of obtaining, yield 36.5%, 208～210 DEG C of m.p..
Embodiment 11
6-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
20 mmol m-nitrobenzaldehydes, 25 mmol thiocarbamides, 20 mL ethanol and the 0.5 mL vitriol oil, stirring and refluxing, drips 16.6 mmol methyl aceto acetates, TLC monitoring reaction course, react 19.5 h, cooling reaction solution, separates out light yellow solid, filter, a small amount of ethanol is washed, dry 6-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-3,4-dihydro-pyrimidin-2-thioketones of obtaining, yield 10.9%, 206～209 DEG C of m.p..
Embodiment 12
6-methyl-4-(4-nitrophenyl)-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
20 mmol paranitrobenzaldehydes, 25 mmol thiocarbamides, 15 mL ethanol and the 0.5 mL vitriol oil, stirring and refluxing, drip 16.6 mmol methyl aceto acetates, TLC monitoring reaction course, react 21 h, revolve steaming solvent, obtain thick shape solid, add the mixed solution of a small amount of sherwood oil and ethyl acetate, stirring is placed in that frozen water is cold to be put, separate out yellow solid, filter, a small amount of ethanol is washed, dry 6-methyl-4-(4-nitrophenyl)-5-ethoxycarbonyl-3 that obtain, 4-dihydro-pyrimidin-2-thioketones, yield 21.8%, 190～193 DEG C of m.p..
Embodiment 13
6-methyl-4-(2-p-methoxy-phenyl)-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
20 mmol o-methoxybenzaldehydes, 25 mmol thiocarbamides, 20 mL ethanol and the 0.5 mL vitriol oil, stirring and refluxing, drips 16.6 mmol methyl aceto acetates, TLC monitoring reaction course, react 7 h, cooling reaction solution, separates out solid, filter, a small amount of ethanol is washed, dry 6-methyl-4-(2-p-methoxy-phenyl)-5-ethoxycarbonyl-3,4-dihydro-pyrimidin-2-thioketones of obtaining, yield 44.1%, 184～187 DEG C of m.p..
Embodiment 14
6-methyl-4-(3-methoxyl group-4-hydroxy phenyl)-5-ethoxycarbonyl-3, the preparation of 4-dihydro-pyrimidin-2-thioketones
20 mmol 3-methoxyl group 4-hydroxy benzaldehydes, 25 mmol thiocarbamides, 15 mL ethanol and the 0.5 mL vitriol oil, stirring and refluxing, drips 16.6 mmol methyl aceto acetates, TLC monitoring reaction course, react 16.5 h, cooling reaction solution, separates out white solid, filter, a small amount of ethanol is washed, dry 6-methyl-4-(3-methoxyl group-4-hydroxy phenyl)-5-ethoxycarbonyl-3, the 4-dihydro-pyrimidin-2-thioketones of obtaining, yield 24.2%, 222～224 DEG C of m.p..
Embodiment 15
4-alkyl-6-aryl-3, the active mensuration of antidepressant (it is active that SERT suppresses) of 4-dihydro-pyrimidin-2-thioketones
1. SERT suppresses determination of activity principle
Fluorescence dye ASP
+that one has neurovirulent compound, can be combined and enter in cell with the transporter of monoamine, and send yellow fluorescence (the strong and weak order of combination is DAT > suprarenin transporter >5-HT transporter).When exist other can with transporter binding compounds, while being at war with ASP, entering intracellular ASP quantity and reduce, yellow fluorescence weakens, and acts on the reuptake inhibitor of 5-HT transporter by the variation screening of fluorescence intensity relatively.
RBL-2H3 cell is a kind of cell strain that can secrete histamine and 5-HT, and this cell is the mastocyte of immortalization, can discharge aforesaid mediator by quantum; And there is SERT and can carry out 5-HT reuptake.
CACO-2 cell is the adenocarcinoma cell strain that derives from people's small intestine, find under study for action can express multiple transporter and acceptor through this cell of cultivation differentiation for some time, comprise SERT, Adenosine Receptors etc., by setting up the standardisation process of cell cultures, make cell after 6 ~ 7 days, can realize well differentiated in cultivation, by adding in advance trial-product for some time to be screened, adding fluorescence dye according to finite concentration, by the dyestuff that does not enter cell is washed away, the fluorescence intensity of ASP between more different samples, can find direct inhibition SERT activity, or pass through the sample of the effect remote effect transporter activity that activates/suppress Adenosine Receptors.
2. experiment equipment
Cell: RBL-2H3, CACO-2 clone, from institute of Materia Medica,Chinese Academy of Medical Sciences national drug screening center.
Reagent: (1) cell culture medium; (2) fluorescence dye ASP.
Instrument: continuous spectrum enzyme mark tester (spectramaxM5) moleculardevices company produces.
3. schedule of operation
3.1 cell cultures
RBL cell strain is purchased from Chinese Typical Representative culture collection center.This cell strain uses containing 1.5g/L sodium bicarbonate, 0.1mM non-essential amino acid, 1.0mM Sodium.alpha.-ketopropionate, the EMEM of 2mML-glutamine and Earle'sBSS, 85%; The substratum of hot deactivation FBS15% carries out cell cultures.The next day that cell needing, change liquid 1 time, when cell proliferation reaches 80%, need go down to posterity, ratio is 1: 3.
Cell cultures: strict aseptic technique, carry out cell cultures with the MEM α perfect medium containing 15% foetal calf serum, reaching logarithmic phase until cell tests time in good condition, wash twice with D-hanks liquid, add 0.125% trypsin digestion cell, place 5min at 37 DEG C, iuntercellular is connected and open, the single distribution of cell, adds equal-volume perfect medium to stop digestion, blow and beat gently cell suspension is placed in to centrifuge tube with 800 turn/min, centrifugal 3min, supernatant discarded, with perfect medium re-suspended cell, count, diluting cells reaches 6 × 10
5individual/ml is for subsequent use.
Cell bed board and dosing, add fluorescence dye: 4 × 10
5individual/ml cell suspension, according to 0.1ml/ hole, adds 96 orifice plates, more than treating cell attachment growth 10h, can carry out the experiment of fluorescence high flux screening when well-grown, and at excitation wavelength 475nm, emission wavelength 605nm place reading, carries out result statistics.
CACO-2 cell strain institute of Materia Medica,Chinese Academy of Medical Sciences national drug screening centralab preserves.This cell strain uses containing 1.5g/L sodium bicarbonate, 0.1mM non-essential amino acid, 1.0mM Sodium.alpha.-ketopropionate, the EMEM of 2mML-glutamine and Earle'sBSS, 80%; The substratum of hot deactivation FBS20% carries out cell cultures.The next day that cell needing, change liquid 1 time, when cell proliferation reaches 80%, need go down to posterity, ratio is 1: 3.
3.2 cell bed board and differentiation
Cell is according to 1 × 10
5/ ml, every hole 100ul adds at the bottom of 96 hole black in transparent culture plate, changes liquid once next day of when cell does not cover with, treat that Growth of Cells is rapid, cover with bottom, need every day and change liquid, treat its differentiation, the visible cell cell boundary on the 6th ~ 7 of growing is unclear, growth microvillus, can carry out the experiment of fluorescence high flux screening, at excitation wavelength 475nm, emission wavelength 605nm place reading, carries out result statistics.
4. data processing
Calculate fluorescence intensity inhibiting rate:
5. detect sample
4-alkyl-6-aryl-3,4-dihydro-pyrimidin-2-thioketones, the SERT transporter inhibitors screening model of all setting up by RBL-2H3 cell screening.
6. evaluation of result
In the time that concentration is 10.0mg/L, screening 4-alkyl-6-aryl-3, the inhibiting rate of 4-dihydro-pyrimidin-2-thioketones to SERT, outstanding compound is 6-methyl-4-(4-chloro-phenyl-)-5-ethoxycarbonyl-3,4-dihydro-pyrimidin-2-thioketones.In the time that concentration is 10.0mg/L, outstanding compound 6-methyl-4-(4-chloro-phenyl-)-5-ethoxycarbonyl-3,4-dihydro-pyrimidin-2-thioketones is 59.2% to the inhibiting rate of SERT; In the time that concentration is 0.0293mmol/L, 6-methyl-4-(4-chloro-phenyl-)-5-ethoxycarbonyl-3,4-dihydro-pyrimidin-2-thioketones is 61.0% to the inhibiting rate of SERT; 6-methyl-4-(4-chloro-phenyl-)-5-ethoxycarbonyl-3, the inhibition activity of 4-dihydro-pyrimidin-2-thioketones to SERT, IC
50for 0.00697mmol/L.
4-alkyl-6-aryl-3, it is active that 4-dihydro-pyrimidin-2-thioketones has good inhibition to SERT, can be used as the application of preparing antidepressant drug.
Claims (2)
1. 4-alkyl-6-aryl-3 shown in chemical structural formula I, 4-dihydro-pyrimidin-2-thioketones and pharmaceutically acceptable salt are in the application of preparing in antidepressant drug:
Wherein, R
1be selected from: C
1～C
2alkyl, C
3～C
4straight chained alkyl or branched-chain alkyl; R is selected from: CH
3or C
2h
5; X
1be selected from: methyl, ethyl, methoxy or ethoxy; X
2be selected from: methyl, ethyl, methoxyl group, oxyethyl group or nitro; X
3be selected from: methyl, ethyl, chlorine, bromine, fluorine, hydroxyl, methoxyl group, oxyethyl group or nitro; X
4be selected from: methyl, ethyl, methoxyl group, oxyethyl group or nitro.
2. application as claimed in claim 1,4-alkyl-6-aryl-3 shown in its Chinese style I, 4-dihydro-pyrimidin-2-thioketones is selected from following compounds:
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87103225A (en) * | 1986-04-29 | 1987-11-11 | 美国辉瑞有限公司 | Antidepressant calcium independent cyclic amp (CAMP) phosphodiesterase inhibitor |
-
2012
- 2012-06-15 CN CN201210198757.7A patent/CN102731411B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87103225A (en) * | 1986-04-29 | 1987-11-11 | 美国辉瑞有限公司 | Antidepressant calcium independent cyclic amp (CAMP) phosphodiesterase inhibitor |
Non-Patent Citations (2)
| Title |
|---|
| 《Three-component condensation. Synthesis and characterization of bioactive 4-substituted aryl pyrimidinones and pyrimidinethiones》;SHAIFALI VERMA et al;《ORIENTAL JOURNAL OF CHEMISTRY》;20111231;第27卷(第3期);第1094页 * |
| SHAIFALI VERMA et al.《Three-component condensation. Synthesis and characterization of bioactive 4-substituted aryl pyrimidinones and pyrimidinethiones》.《ORIENTAL JOURNAL OF CHEMISTRY》.2011,第27卷(第3期),第1094页. |
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